Hypocretin/orexin deficiency decreases cocaine abuse liability.

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Version: Author's accepted manuscript
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_C7C6341D69D0
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Hypocretin/orexin deficiency decreases cocaine abuse liability.
Journal
Neuropharmacology
Author(s)
Steiner N., Rossetti C., Sakurai T., Yanagisawa M., de Lecea L., Magistretti P.J., Halfon O., Boutrel B.
ISSN
1873-7064 (Electronic)
ISSN-L
0028-3908
Publication state
Published
Issued date
01/05/2018
Peer-reviewed
Oui
Volume
133
Pages
395-403
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Compelling evidence indicates that hypocretin/orexin signaling regulates arousal, stress and reward-seeking behaviors. However, most studies on drug reward-related processes have so far described the effects of pharmacological blockers disrupting hypocretin/orexin transmission. We report here an extensive study on cocaine-related behaviors in hypocretin/orexin-deficient mice (KO) and their heterozygous (HET) and wildtype (WT) littermates. We evaluated behavioral sensitization following repeated administrations and preference for an environment repeatedly paired with cocaine injections (15 mg/kg). Mice were also trained to self-administer cocaine (0.5-1.5 mg/kg/infusion). Our observations show that whereas all mice exhibited quite similar responses to acute administration of cocaine, only Hcrt KO mice exhibited reduced cocaine-seeking behaviors following a period of abstinence or extinction, and reduced cocaine incubation craving. Further, if the present findings confirm that Hcrt deficient mice may display a hypoactive phenotype, possibly linked to a reduced alertness concomitant to a decreased exploration of their environment, hypocretin/orexin defiency did not cause any attentional deficit. We thus report that innate disruption of hypocretin/orexin signaling moderately alters cocaine reward but significantly reduces long-term affective dependence that may explain the lack of relapse for cocaine seeking seen in Hcrt KO mice. Overall, with blunted cocaine intake at the highest concentration and reduced responsiveness to cocaine cues after prolonged abstinence, our findings suggest that hypocretin deficient mice may display signs of resilience to cocaine addiction.
Keywords
Analysis of Variance, Anesthetics, Local/administration & dosage, Anesthetics, Local/pharmacology, Animals, Cocaine/administration & dosage, Cocaine/pharmacology, Cocaine-Related Disorders/genetics, Cocaine-Related Disorders/physiopathology, Conditioning, Operant/drug effects, Cues, Dose-Response Relationship, Drug, Drug-Seeking Behavior/drug effects, Drug-Seeking Behavior/physiology, Extinction, Psychological/drug effects, Female, Locomotion/drug effects, Locomotion/genetics, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Orexins/deficiency, Orexins/genetics, Reward, Saccharin/administration & dosage, Self Administration, Time Factors, Cocaine, Hypocretin, Motivation, Orexin, Relapse, Saccharine
Pubmed
Web of science
Create date
01/03/2018 14:32
Last modification date
20/08/2019 16:43
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